Abstract & Commentary
Source: Nemni R, et al. Peripheral neuropathy in hepatitis C virus infection with and without cryoglobulinemia. J Neurol Neurosurg Psychiatry. 2003;74:1267-1271.
Fifty-one consecutive hepatitis c patients with neuropathy were evaluated to determine whether, and by what mechanism, cryoglobulinemia was associated with peripheral neuropathy. None demonstrated other causes of neuropathy including diabetes, alcoholism, renal failure, vitamin deficiency, toxicity, thyroid disease, or neoplasia. All underwent clinical, serologic, and electrodiagnostic study, with 28 agreeing to sural nerve biopsy. Statistical analysis used X2 testing, with Yates’ correction if required, and students’ t tests. Significance was defined by a P value < .01 and < .05.
Among the 25 men and 26 women, mean age was 62 years at the time of diagnosis. Forty (78%) were cryoglobulin positive (CG+), and all demonstrated mixed cryoglobulinemia, while 11 showed no cryoglobulins (CG-). Peripheral neuropathy was significantly more common in the CG+ group, whereas cranial neuropathy was more common in the CG- patients. Mononeuropathy multiplex was seen equally in both groups. CG+ patients more often had low C4 levels and rheumatoid factor positivity. Transaminase activity was increased in both. Motor and sensory nerve conduction studies were similar in both groups, with only the deep peroneal motor conduction velocity being significantly slowed in the CG+ group but not into the demyelinating range. Sural nerve biopsy findings were not significantly different in the 2 groups. Of 25 CG+ patients who underwent biopsy, axonal loss was seen in 10 (40%), epineurial vasculitis in 8 (32%), and both axonal and demyelinating changes in 7 (28%). Of 3 CG- patients who were biopsied, 2 showed epineurial vasculitis and the third, axonal loss. None of the 28 biopsies revealed primary demyelination on teased fiber preparation. Cryoglobulin positivity in hepatitis C virus (HCV) infection is associated with peripheral neuropathy. Ischemic injury, rather than direct viral invasion, is the more likely pathomechanism.
Commentary
HCV, the most common cause of non-A, non-B hepatitis, is a single-stranded, enveloped RNA virus of the Flaviviridae family. Nine genotypes with associated subtypes exist, but genotype 1b is the culprit least treatable and most correlated with severe clinical disorders.1 Neurologically, these include peripheral nerve vasculitis, ischemic and hemorrhagic stroke, cerebral vasculitis, myelitis, encephalitis, and, rarely, lymphoma.2 High-risk behavior is generally necessary for contracting HCV, including exposure to blood or its products, sexual activity, and IV drug use, but household contact and perinatal exposure are also reported.3
Cryoglobulins, serum proteins that reversibly precipitate at low temperature, are classified as type 1 (monoclonal immunoglobulins), type II (polyclonal and monoclonal immunoglobulins), and type III (polyclonal immunoglobulins). In the absence of a lymphoproliferative disorder, types II and III are termed mixed essential cryoglobulins and are often associated with HCV infection wherein associated neurologic complications are strongest. HCV also promotes production of rheumatoid factor (RF). Cryoglobulins associated with HCV can activate complement resulting in hypocomplementemia with formation of immunoglobulin/RF cryoprecipitates that may, in turn, trigger vasculitis and its associated clinical sequelae. Treatment includes corticosteroids, immunosuppressive agents, and plasma exchange but remains challenging with frequent relapses and rare long-term remissions.4 — Michael Rubin
Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.
References
1. Gordon SC. Dig Dis. 1996;14:157-168.
2. Khella SL, Souayah N. The Neurologist. 2002;8: 101-106.
3. N Engl J Med. 1999;340:300-307.
4. Rieu V, et al. Rheumatology. 2002;41:290-300.
Fifty-one consecutive hepatitis c patients with neuropathy were evaluated to determine whether, and by what mechanism, cryoglobulinemia was associated with peripheral neuropathy.
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